Kabachnik-Fields Reaction

This
three-component coupling of a carbonyl, an amine and a hydrophosphoryl
compound leads to α-aminophosphonates. The Kabachnik-Fields Reaction is
very important in drug discovery research for generating peptidomimetic
compounds.

Early
protocols were limited to simple starting materials (for example
aldehydes) but newer methods permit reactions to take place even with
sterically demanding starting materials.

Mechanism of the Kabachnik-Fields Reaction

The pathway of the Kabachnik-Fields reaction depends on the nature of the
substrates. The amine and hydrophosphoryl compound form a complex in which
either one of the partners may react with the carbonyl compound. Often, the
basicity of the amine determines the reaction pathway. Weakly basic amines such
as anilines, which can act as proton donors, favour the formation of an imine,
whereas alkylamines such as cyclohexylamines do not form imines:

If additional catalysts are used, both acids and bases can have a positive
influence on the reaction rate. Sometimes, the chemical yield and the
diastereoselectivity of the formation of α-aminophosphonates are higher in
two-component systems using preformed imines. In this case, due to the
phosphonate <-> phosphite tautomerism, the addition to the imine could occur by
either a four- or five-membered transition state:

A more detailed discussion of the mechanism of the Kabachnik-Fields reaction,
its synthetic potential and the biological activity of the α-aminophosphonates
can be found in a review by R. A. Cherkasov and V. I. Galkin (Russ.
Chem. Rev.1998, 67, 857-882.
DOI)

An interesting recent publication of an enantioselective transformation using
quinine as an organocatalyst suggests the following transition state:

As this example shows a high degree of complexity, one can imagine that the
design of an enantioselective three-component reaction would be somewhat more
difficult, and it is clear that some basic investigation into the stereocontrol
of the Kabachnik-Fields reaction is still needed.